The current model of melanoma formation is that melanocytes progress from a normal to malignant state by accumulating mutations in key melanoma genes. See, Meier, F., et al. (1998) Frontiers in Bioscience 3:D1005-1010. Melanoma can arise spontaneously, or within a pre-existing nevus or mole. Nevi possess mutations in known melanoma genes and are therefore a risk factor for developing melanoma. See, e.g., Pollock, P. M., et al., (2003) Nat. Genet. 33(1):19-20; Kumar, R. et al., (2004) J. Invest. Dermatol. 122(2):342-348; Chin, L., (2003) Nat. Rev. Cancer 3(8):559-570.
The majority of human melanomas and melanocytic nevi have been shown to have activating mutations in the BRAF, NRAS, C-KIT, or HRAS genes. Furthermore, recent studies have demonstrated that melanomas fall into genetically distinct groups having marked differences in the frequency of MAP-kinase pathway activation. See, Curtin, J. A., et al., (2005) N Engl J Med. 353(20):2135-47. One category, uveal melanoma, arises from melanocytes within the choroidal plexus of the eye and is biologically distinct from cutaneous melanoma by characteristic cytogenetic alterations. See, Horsman et al. (1993) Cancer 71(3):811. The other category are intradermal melanocytic proliferations, which can be congenital or acquired, and present in diverse ways ranging from discrete bluish moles (blue nevi) to large blue-gray patches affecting the conjunctiva and periorbital skin (nevus of Ota), shoulders (nevus of Ito), and the lower back (Mongolain spot). See, Zembowicz, et al. (2004) Histopathology 45(5):433. These intradermal melanocytic proliferations do not contain either BRAF or NRAS mutations, and thus have a unique eitiology when compared with other nevi and melanoma. See, Ariyanayagam-Baksh S M, et al., (2003) Am J Dermatopathol. 25(1): p. 21-7.
Uveal melanoma is a melanocytic neoplasm that arises from melanocytes in the choroidal plexus, ciliary body or iris epithelium of the eye (e.g., Singh, et al., Ophthalmol Clin North Am 18:75-84, viii, 2005). In more aggressive subtypes there are further genetic alterations such as monosomy 3, trisomy 8 and a strong tendency to metastasize to the liver (Singh, et al., Ophthalmol Clin North Am 18:75-84, viii, 2005, Horsman & White, Cancer 71:811-9, 1993). Uveal melanoma is highly aggressive, with a 5-year disease-specific survival rate of approximately 70% (e.g., Chang et al., Cancer 83:1664-78, 1998). One risk factor for uveal melanoma is the presence of bluish-grey hyper-pigmentation in the conjunctiva and periorbital dermis, called the naevus of Ota (Singh et al., Ophthalmology 105:195-8, 1998). (1998) Am J Dermatopathol. 20:109-110).
Recently, a large-scale mutagenesis screen in mice identified several dark skin (Dsk) mutants. See, Van Raamsdonk C D, et al., (2004) Nat Genet. 36: 961-968. Some of these mutants had a melanocytic phenotype with a sparse cellular proliferation of intradermal melanocytes resembling blue nevi. The mutations were shown to be the result of mutations in G-protein α-subunits.
G proteins represent a large family of heterotrimeric proteins found in mammals composed of alpha (α), beta (β) and gamma (γ) subunits. See, Wettschureck, N. A. O. S., (2005) Physiol. Rev. 85(4):1159-1204. G-αq, is one of a variety of G-alpha subunits that mediates the stimulation of phospholipase Cβ through the binding and hydrolysis of GTP. See, Markby, D. W., et al., (1993) Science 262(1541):1895-1901. It has been hypothesized that activation of G-αq promotes the survival of melanocytes in the dermis. See, Van Raamsdonk, C. D., et al., (2004). This is consistent with the observation in mice that hyperactivity of G-αq increases the number of melanoblasts, immature melanocytes, migrating in the dermis without increasing their mitotic rate. See, Van Raamsdonk, C. D., et al., (2004).
Somatic oncogenic mutations of GNAQ, a heterotrimeric G protein alpha subunit, have been identified in various melanocytic neoplasms, including blue nevi and uveal melanomas (WO 2008/098208), among others.
GNA11 is 90% identical to GNAQ at the amino acid level and shares overlapping functions with GNAQ on pigmentation in mice. This invention is based, in part, on the discovery of the occurrence of mutations in GNA11 in melanocytic neoplasms, including in uveal melanoma.